A terphenyl derivative-based colorimetric-fluorimetric probe for the detection of lysine and arginine and their bioimaging.

Lysine (Lys) and arginine (Arg) play a crucial role in the human diets, medical diagnostics, and functional biomaterial synthesis. The imbalance of intake for these two amino acids causes various diseases. Although many analytical techniques have been reported for the detection of amino acids, there are still some issues such as the need for bulky instruments, professional operators, sensitivity to be improved, and real-time detection. Here, a novel colorimetric-fluorimetric probe based on a terphenyl derivative (TPT) has been synthesized for the precise detection of Lys and Arg. In the EtOH-H2O solution of TPT, the NH2 group at the chain end of Lys/Arg undergoes a nucleophilic addition reaction with CN groups of benzothiazole groups of the probe TPT, which breaks the initial long-conjugated system of the probe molecule. As a result, blue shifts can be observed for both UV-vis absorption spectra and fluorescence spectra, accompanying with color changes of the TPT solution. The UV-vis absorption peak of TPT solution shifts from âˆ¼410 nm to âˆ¼325 nm, and the solution color changes from light-yellow to colorless. The fluorescence emission shifts from âˆ¼580 nm to âˆ¼470 nm and the bright-yellow TPT solution changes to blue under the irradiation of 365 nm UV light. For colorimetric method, the limits of detection (LoD) are 0.82 µM and 0.90 µM for Lys and Arg, respectively. For fluorimetric method, they are 2.02 nM and 1.62 nM for Lys and Arg, respectively. In addition, TPT has good selectivity and anti-interference for Lys and Arg. The synthesized probe TPT has been successfully used for the precise detection of Lys and Arg in drugs and for fluorescence imaging of living cells. This work demonstrates that terphenyl-based derivatives are promising organic probes for the detection of Lys and Arg, providing a new way for designing other amino acids probes.

Increased brain volume in the early phase of aneurysmal subarachnoid hemorrhage leads to delayed cerebral ischemia.

Objective: To investigate the correlation between the swelling rate of brain volume within the first 48 h after aneurysmal subarachnoid hemorrhage and the subsequent development of delayed cerebral ischemia. Methods: A retrospective analysis was conducted on patients with spontaneous aneurysmal subarachnoid hemorrhage admitted to the Neurosurgery Intensive Care Unit of the First Affiliated Hospital of Chongqing Medical University between January 2020 and January 2023. The clinical data, treatment outcomes, and imaging data were analyzed. Brain volume was evaluated using 3D-Slicer software at two time points post-hemorrhage: within the first 24 h and between 24 and 48 h. The swelling rate of brain volume was defined as the ratio of the absolute difference between two measurements to the smaller of values. Patients were categorized into two groups based on established diagnostic criteria of delayed cerebral ischemia. Univariate and multivariate logistic regression analyses were performed to identify factors influencing delayed cerebral ischemia. Results: A total of 140 patients were enrolled in this study. 46 patients experienced delayed cerebral ischemia after bleeding. The swelling rate of brain volume was larger in the DCI group (10.66 ± 8.45) compared to the non-DCI group (3.59 ± 2.62), which showed a statistically significant difference. Additionally, advanced age, smoking history, history of hypertension, loss of consciousness, poor Hunt-Hess grade, high mFisher score, brain volume within 24 h, and IVH were also statistically different between the two groups. Multivariate logistic regression analysis revealed that the swelling rate of brain volume was an independent risk factor for DCI with adjusting the advanced age, smoking history, history of hypertension, poor Hunt-Hess grade, high mFisher score, brain volume within 24 h, and IVH. Conclusion: Brain volume significantly increased in patients with aneurysmal subarachnoid hemorrhage during the early phase (within 48 h post-onset). The larger swelling rate of brain volume is an independent risk factor for the development of delayed cerebral ischemia, and it may hold significant predictive value for the incidence of delayed cerebral ischemia.

A review of KLF4 and inflammatory disease: Current status and future perspective.

Inflammation is the response of the human body to injury, infection, or other abnormal states, which is involved in the development of many diseases. As a member of the Krüppel-like transcription factors (KLFs) family, KLF4 plays a crucial regulatory role in physiological and pathological processes due to its unique dual domain of transcriptional activation and inhibition. A growing body of evidence has demonstrated that KLF4 plays a pivotal role in the pathogenesis of various inflammatory disorders, including inflammatory bowel disease, osteoarthritis, renal inflammation, pneumonia, neuroinflammation, and so on. Consequently, KLF4 has emerged as a promising new therapeutic target for inflammatory diseases. This review systematically generalizes the molecular regulatory network, specific functions, and mechanisms of KLF4 to elucidate its complex roles in inflammatory diseases. An in-depth study on the biological function of KLF4 is anticipated to offer a novel research perspective and potential intervention strategies for inflammatory diseases.

Association between admission serum potassium concentration and the island sign on cranial CT in HICH patients: a cross-sectional study.

Objective: This study aimed to explore the correlation between serum potassium (K+) concentration upon admission and the presence of the Island Sign (IS) in cranial CT scans of patients diagnosed with Hypertensive Intracerebral Hemorrhage (HICH), including the potential presence of a non-linear relationship. Methods: This investigation constituted a single-center cross-sectional study. We systematically gathered comprehensive general clinical characteristics, biological indicators, and imaging data from a cohort of 330 patients diagnosed with HICH. These patients received treatment within the neurosurgery department of Chongqing Emergency Medical Center during the period spanning from July 1, 2018, to July 7, 2023. Our primary objective was to scrutinize the potential connection between serum K+ concentration upon admission and the presence of the IS observed in cranial CT scans. To meticulously address this inquiry, we employed logistic regression modeling, thereby meticulously evaluating the correlation aforementioned. Moreover, in order to delve deeper into the intricacies of the relationship, we extended our analysis by employing a smoothed curve-fitting model to meticulously authenticate the potential non-linear interrelation between these two critical variables. Results: In this investigation, a total of 330 patients diagnosed with HICH were ultimately enrolled, exhibiting an average age of 58.4 ± 13.1 years, comprising 238 (72.1%) males and 92 (27.9%) females. Among these participants, 118 individuals (35.7%) presented with the IS upon admission cranial CT scans, while 212 patients (64.3%) did not exhibit this characteristic. Upon comprehensive multifactorial adjustments, a non-linear association was uncovered between serum K+ concentration and the presence of IS. Notably, an inflection point was identified at approximately 3.54 mmol/L for serum K+ concentration. Prior to the patient's serum K+ concentration reaching around 3.54 mmol/L upon admission, a discernible trend was observed-every 0.1 mmol/L increment in serum K+ concentration was associated with an 8% decrease in the incidence of IS (OR: 0.914, 95% CI: 0.849-0.983, p = 0.015). Conclusion: The findings of this study underscore a negative association between reduced serum K+ concentration upon admission and the occurrence of the IS on cranial CT scans among patients diagnosed with hypertensive cerebral hemorrhage. Furthermore, this negative correlation appears to manifest within the realm of a non-linear relationship. This study elucidates the potential significance of serum K+ concentration levels among patients with HICH, highlighting the role they play. Moreover, the maintenance of a physiological equilibrium in serum K+ concentrations emerges as a conceivable protective factor for individuals within the stroke population.

Selective Activation of G Protein-Coupled Estrogen Receptor 1 (GPER1) Reduces ER Stress and Pyroptosis via AMPK Signaling Pathway in Experimental Subarachnoid Hemorrhage.

Neuroinflammation is a critical pathogenic event following hemorrhagic stroke. Endoplasmic reticulum (ER) stress-induced apoptosis and nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3(NLRP3)-associated pyroptosis can contribute to the escalation of neuroinflammatory responses, leading to increased brain damage. G protein-coupled estrogen receptor 1(GPER1), as the most extensively characterized brain-derived estrogen, was reported to trigger neuroprotective effects. However, the anti-apoptotic and anti-pyroptotic effect of GPER1 activation and the underlying mechanism has not been fully elucidated. We established the experimental SAH model by intravascular perforation. The GPER1 selective agonist G1 was intravenously administered 1 h following SAH. For mechanistic exploration, the selective inhibitor of adenosine monophosphate-activated protein kinase (AMPK), dorsomorphin, was administered via intracerebroventricular injection 30 min prior to SAH induction. Post-SAH assessments included SAH grade, the short-term and long-term neurological outcomes, brain edema, cerebral blood flow, transmission electron microscopy (TEM), western blot (WB), ELISA, TUNEL staining, Fluoro-Jade C staining (FJC), and immunofluorescence staining. The expression of GPER1 was observed to elevate at 6 h and peaked at 24 h subsequent to SAH, predominantly co-localized with neurons. Post-treatment with G1 markedly ameliorated both the short-term and long-term neurological deficits of SAH mouse, as well as inhibiting the expression of neuronal ER stress-associated apoptotic proteins (i.e., CHOP, GRP78, Caspase-12, Cleaved Caspase-3, Bax, Bcl2) and pyroptosis-associated proteins (i.e., NLRP3, ASC, Cleaved Caspase-1). Additionally, our research revealed that inhibition of AMPK with dorsomorphin attenuated the neuroprotective effects of G1. This was accompanied by modifications in the molecular pathways associated with ER stress-induced apoptosis and pyroptosis. These data herein elucidated that GPER1 exerted neuroprotective effects by mitigating neuroinflammation in an AMPK-dependent manner, which modulates neuronal ER stress-associated apoptosis and pyroptosis. Boosting the anti-apoptotic and anti-pyroptotic effect by activating GPER1 may be an efficient treatment strategy for SAH patients.

Ultrasound combined with urokinase under key-shaped bone window enhances blood clot lysis in an in vitro model of spontaneous intracerebral hemorrhage.

OBJECTIVE: Minimally invasive surgery for spontaneous intracerebral hemorrhage is impeded by inadequate lysis of the target blood clot. Ultrasound is thought to expedite intravascular thrombolysis, thereby facilitating vascular recanalization. However, the impact of ultrasound on intracerebral blood clot lysis remains uncertain. This study aimed to explore the feasibility of combining ultrasound with urokinase to enhance blood clot lysis in an in vitro model of spontaneous intracerebral hemorrhage. METHODS: The blood clots were divided into four groups: control group, ultrasound group, urokinase group, and ultrasound + urokinase group. Using our experimental setup, which included a key-shaped bone window, we simulated a minimally invasive puncture and drainage procedure for spontaneous intracerebral hemorrhage. The blood clot was then irradiated using ultrasound. Blood clot lysis was assessed by weighing the blood clot before and after the experiment. Potential adverse effects were evaluated by measuring the temperature variation around the blood clot in the ultrasound + urokinase group. RESULTS: A total of 40 blood clots were observed, with 10 in each experimental group. The blood clot lysis rate in the ultrasound group, urokinase group, and ultrasound + urokinase group (24.83 ± 4.67%, 47.85 ± 7.09%, 61.13 ± 4.06%) was significantly higher than that in the control group (16.11 ± 3.42%) (p = 0.02, p < 0.001, p < 0.001). The blood clot lysis rate in the ultrasound + urokinase group (61.13 ± 4.06%) was significantly higher than that in the ultrasound group (24.83 ± 4.67%) (p < 0.001) or urokinase group (47.85 ± 7.09%) (p < 0.001). In the ultrasound + urokinase group, the mean increase in temperature around the blood clot was 0.26 ± 0.15°C, with a maximum increase of 0.38 ± 0.09°C. There was no significant difference in the increase in temperature regarding the main effect of time interval (F = 0.705, p = 0.620), the main effect of distance (F = 0.788, p = 0.563), or the multiplication interaction between time interval and distance (F = 1.100, p = 0.342). CONCLUSIONS: Our study provides evidence supporting the enhancement of blood clot lysis in an in vitro model of spontaneous intracerebral hemorrhage through the combined use of ultrasound and urokinase. Further animal experiments are necessary to validate the experimental methods and results.

ISRIB improves white matter injury following TBI by inhibiting NCOA4-mediated ferritinophagy.

Traumatic brain injury (TBI) often results in persistent neurological dysfunction, which is closely associated with white matter injury. The mechanisms underlying white matter injury after TBI remain unclear. Ferritinophagy is a selective autophagic process that degrades ferritin and releases free iron, which may cause ferroptosis. Although ferroptosis has been demonstrated to be involved in TBI, it is unclear whether ferritinophagy triggers ferroptosis in TBI. Integrated stress response inhibitor (ISRIB) has neuroprotective properties. However, the effect of ISRIB on white matter after TBI remains uncertain. We aimed to investigate whether ferritinophagy was involved in white matter injury following TBI and whether ISRIB can mitigate white matter injury after TBI by inhibiting ferritinophagy. In this study, controlled cortical impact (CCI) was performed on rats to establish the TBI model. Ferritinophagy was measured by assessing the levels of nuclear receptor coactivator 4 (NCOA4), which regulates ferritinophagy, ferritin heavy chain 1(FTH1), LC3, ATG5, and FTH1 colocalization with LC3 in the white matter. Increased NCOA4 and decreased FTH1 were detected in our study. FTH1 colocalization with LC3 enhanced in the white matter after TBI, indicating that ferritinophagy was activated. Immunofluorescence co-localization results also suggested that ferritinophagy occurred in neurons and oligodendrocytes after TBI. Furthermore, ferroptosis was assessed by determining free iron content, MDA content, GSH content, and Perl's staining. The results showed that ferroptosis was suppressed by NCOA4 knockdown via shNCOA4 lentivirus infection, indicating that ferroptosis in TBI is triggered by ferritinophagy. Besides, NCOA4 deletion notably improved white matter injury following TBI, implying that ferritinophagy contributed to white matter injury. ISRIB treatment reduced the occurrence of ferritinophagy in neurons and oligodendrocytes, attenuated ferritinophagy-induced ferroptosis, and alleviated white matter injury. These findings suggest that NCOA4-mediated ferritinophagy is a critical mechanism underlying white matter injury after TBI. ISRIB holds promise as a therapeutic agent for this condition.

Predicting Hematoma Expansion and Prognosis in Cerebral Contusions: A Radiomics-Clinical Approach.

Hemorrhagic progression of contusion (HPC) often occurs early in cerebral contusions (CC) patients, significantly impacting their prognosis. It is vital to promptly assess HPC and predict outcomes for effective tailored interventions, thereby enhancing prognosis in CC patients. We utilized the Attention-3DUNet neural network to semi-automatically segment hematomas from computed tomography (CT) images of 452 CC patients, incorporating 695 hematomas. Subsequently, 1502 radiomic features were extracted from 358 hematomas in 261 patients. After a selection process, these features were used to calculate the radiomic signature (Radscore). The Radscore, along with clinical features such as medical history, physical examinations, laboratory results, and radiological findings, was employed to develop predictive models. For prognosis (discharge Glasgow Outcome Scale score), radiomic features of each hematoma were augmented and fused for correlation. We employed various machine learning methodologies to create both a combined model, integrating radiomics and clinical features, and a clinical-only model. Nomograms based on logistic regression were constructed to visually represent the predictive procedure, and external validation was performed on 170 patients from three additional centers. The results showed that for HPC, the combined model, incorporating hemoglobin levels, Rotterdam CT score of 3, multi-hematoma fuzzy sign, concurrent subdural hemorrhage, international normalized ratio, and Radscore, achieved area under the receiver operating characteristic curve (AUC) values of 0.848 and 0.836 in the test and external validation cohorts, respectively. The clinical model predicting prognosis, utilizing age, Abbreviated Injury Scale for the head, Glasgow Coma Scale Motor component, Glasgow Coma Scale Verbal component, albumin, and Radscore, attained AUC values of 0.846 and 0.803 in the test and external validation cohorts, respectively. Selected radiomic features indicated that irregularly shaped and highly heterogeneous hematomas increased the likelihood of HPC, while larger weighted axial lengths and lower densities of hematomas were associated with a higher risk of poor prognosis. Predictive models that combine radiomic and clinical features exhibit robust performance in forecasting HPC and the risk of poor prognosis in CC patients. Radiomic features complement clinical features in predicting HPC, although their ability to enhance the predictive accuracy of the clinical model for adverse prognosis is limited.

Deferoxamine reduces endothelial ferroptosis and protects cerebrovascular function after experimental traumatic brain injury.

Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of iron metabolism in neuronal survival, yet its effect on vasculature remains unclear. This study aims to explore the impact of endothelial ferroptosis on cerebrovascular function in TBI. A Controlled Cortical Impact (CCI) model was established in mice, resulting in a significant increase in iron-related proteins such as TfR1, FPN1, and FTH, as well as oxidative stress biomarker 4HNE. This was accompanied by a decline in expression of the ferroptosis inhibitor GPX4. Moreover, Perls' staining and nonhemin iron content assay showed iron overload in brain microvascular endothelial cells (BMECs) and the ipsilateral cortex. Immunofluorescence staining revealed more FTH-positive cerebral endothelial cells, consistent with impaired perfusion vessel density and cerebral blood flow. As a specific iron chelator, deferoxamine (DFO) treatment inhibited such ferroptotic proteins expression and the accumulation of lipid-reactive oxygen species following CCI, enhancing glutathione peroxidase (GPx) activity. DFO treatment significantly reduced iron deposition in BMECs and brain tissue, and increased density of the cerebral capillaries as well. Consequently, DFO treatment led to improvements in cerebral blood flow (as measured by laser speckle imaging) and behavioral performance (as measured by the neurological severity scores, rotarod test, and Morris water maze test). Taken together, our results indicated that TBI induces remarkable iron disorder and endothelial ferroptosis, and DFO treatment may help maintain iron homeostasis and protect vascular function. This may provide a novel therapeutic strategy to prevent cerebrovascular dysfunction following TBI.

Randomized controlled trial on the effects of mindfulness-based respiratory decompression therapy in claustrophobic patients undergoing MRI inspection.

Background: Claustrophobia is a psychological disease. It is estimated to occur in 2.1-14.3% of all magnetic resonance imaging (MRI) examinations. Mindfulness decompression is an effective means to treat and reduce fear and anxiety. There is a rare report on the application of mindfulness-based stress reduction therapy in the magnetic resonance examinations of patients with claustrophobia to date. Purpose: The purpose of this study is to explore the intervention effect of mindfulness respiratory decompression therapy on the MRI inspection of patients with claustrophobia. Methods: A total of 86 patients with claustrophobia requiring MRI in our hospital from January 2018 to December 2020 were divided into two groups. The control group was given routine psychological nursing, and the observation group was given a mindfulness breathing technique on the basis of the control group. Before and after the intervention, we compared the intervention effect, satisfaction with nurses' psychological intervention technique, severe autonomic nervous symptoms during the examination, self-rating anxiety scale (SAS) scores, and profile of mood states revised (POMS-R) scores. Results: The total effective rate of intervention in the observation group was 90.90%, which was significantly higher (χ2 = 6.857, p = 0.00004) than that in the control group (26.19%). Severe autonomic nervous symptoms in the observation group were significantly lower than those in the control group (p < 0.05). After the intervention, SAS scores and POMS-R scores in the observation group decreased with statistical significance (p < 0.05). Conclusion: Mindfulness respiratory decompression therapy can effectively help claustrophobic patients complete an MRI examination, which may be worthy of wide promotion and application in the clinic.

[Risk factors for neonatal asphyxia and establishment of a nomogram model for predicting neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture: a multicenter study]. / æ¹–åŒ—æ©æ–½åœŸå®¶æ—è‹—æ—è‡ªæ²»å·žæ–°ç”Ÿå„¿çª’æ¯å±é™©å› ç´ åˆ†æžåŠåˆ—çº¿å›¾é¢„æµ‹æ¨¡åž‹çš„æž„å»ºï¼šä¸€é¡¹å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture and establish a nomogram model for predicting the risk of neonatal asphyxia. METHODS: A retrospective study was conducted with 613 cases of neonatal asphyxia treated in 20 cooperative hospitals in Enshi Tujia and Miao Autonomous Prefecture from January to December 2019 as the asphyxia group, and 988 randomly selected non-asphyxia neonates born and admitted to the neonatology department of these hospitals during the same period as the control group. Univariate and multivariate analyses were used to identify risk factors for neonatal asphyxia. R software (4.2.2) was used to establish a nomogram model. Receiver operator characteristic curve, calibration curve, and decision curve analysis were used to assess the discrimination, calibration, and clinical usefulness of the model for predicting the risk of neonatal asphyxia, respectively. RESULTS: Multivariate logistic regression analysis showed that minority (Tujia), male sex, premature birth, congenital malformations, abnormal fetal position, intrauterine distress, maternal occupation as a farmer, education level below high school, fewer than 9 prenatal check-ups, threatened abortion, abnormal umbilical cord, abnormal amniotic fluid, placenta previa, abruptio placentae, emergency caesarean section, and assisted delivery were independent risk factors for neonatal asphyxia (P<0.05). The area under the curve of the model for predicting the risk of neonatal asphyxia based on these risk factors was 0.748 (95%CI: 0.723-0.772). The calibration curve indicated high accuracy of the model for predicting the risk of neonatal asphyxia. The decision curve analysis showed that the model could provide a higher net benefit for neonates at risk of asphyxia. CONCLUSIONS: The risk factors for neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture are multifactorial, and the nomogram model based on these factors has good value in predicting the risk of neonatal asphyxia, which can help clinicians identify neonates at high risk of asphyxia early, and reduce the incidence of neonatal asphyxia.

Facile fabrication of an Au/Cu bimetallic nanocluster-based fluorescent composite film for sensitive and selective detection of Cr(VI).

To overcome the disadvantage of simple bimetallic nanocluster solutions being difficult to store and utilize, we prepared and obtained a novel gold and copper bimetallic nanocluster-doped chitosan fluorescent composite film. In this study, gold and copper bimetallic nanoclusters emitting strong red fluorescence were first synthesized by a chemical reduction method. Subsequently, a novel gold and copper bimetallic nanocluster-doped chitosan fluorescent composite film was successfully prepared by a solution casting method. After 60 minutes of UV light irradiation or 30 days at room temperature, the relative fluorescence intensity values of the composite film decreased by 0.9% and 1.2%, respectively. This indicates that its optical properties are stable and that it can be stored for a long time. The composite film has strong and bright red fluorescence and can be used as a fluorescent probe to achieve real-time detection of Cr(VI). It also has a low detection limit for Cr(VI) (0.26 ppb), so it can be applied to the detection of Cr(VI) in actual water samples and get satisfactory detection results. Due to its portability, high selectivity, and high sensitivity, it can also be extended to chemical and food detection.

Effects of Gypenoside XLIX on fatty liver cell gene expression in vitro: a genome-wide analysis.

OBJECTIVE: To perform Genome-wide analysis of Gypenoside XLIX (Gyp-XLIX) in the treatment of fatty liver cells. METHODS: The gene profiles of 3 normal liver cells, 3 fatty liver cells, and 3 fatty liver cells treated with Gyp-XLIX were detected by high-throughput sequencing to identify the differentially expressed genes (DEGs) in fatty liver treated by Gyp-XLIX. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to explore the biological functions of DEGs. By constructing lncRNA-mRNA co-expression network of DEGs, network node genes were mined. Possible target genes of differentially expressed lncRNA were predicted by cis regulation. RESULTS: 782 DEGs were screened out; that is, 172 genes were highly expressed in fatty liver cells, and the expression decreased to the level of normal liver cells after Gyp-XLIX treatment; 610 genes were under expressed in fatty liver cells, and the expression increased to the level of normal liver cells after Gyp-XLIX treatment. Functional analysis of KEGG and GO showed that DEGs process DNA-binding transcription factor activity and ion transmembrane transporter activity in the plasma membrane region. This mediates glycerophospholipid metabolism, bile secretion, fatty acid degradation and other signaling pathways. lncRNA analysis showed that the expression of 16 lncRNAs was low in fatty liver cells, and the expression was increased to the level of normal liver cells after Gyp-XLIX treatment. Target gene prediction showed that 16 differentially expressed lncRNAs had cis potential to regulate target genes, among which lncRNA RPARP-AS1 had a high degree of relationship with other genes. lncRNA-mRNA co-expression network results showed that lncRNA RPARP-AS1 may acted on NFKB2. CONCLUSION: LncRNA was differentially expressed in fatty liver cells and Gyp-XLIX treated fatty liver cells, and lncRNA RPARP-AS1 may be a regulatory gene in Gyp-XLIX treated fatty liver.

Quantification of human embryonic ζ-globin chains in Southeast Asian deletion (--SEA) carriers.

AIMS: Reactivation of embryonic ζ-globin is a promising strategy for genetic treatment of α-thalassaemia. However, quantification of ζ-globin as a quantitative trait in α-thalassaemia carriers and patients remains incompletely understood. In this study, we aimed to set up a reliable approach for the quantification of ζ-globin in α-thalassaemia carriers, followed by a population study to investigate its expression patterns. METHODS: ζ-globin was purified as monomers from cord blood haemolysate of a Hb Bart's fetus, followed by absolute protein quantification, which was then tested by in-house ELISA system and introduced as protein standard. It was then used for large-scale quantification in peripheral blood samples from 6179 individuals. Finally, liquid chromatography-tandem mass spectrometry (LC-MS/MS) introduced as an independent validating approach by measuring ζ-globin expression in a second cohort of 141-SEA/αα carriers. RESULTS: The ELISA system was proved sensitive in distinguishing individuals with varied extent of ζ-globin. Large scale quantitative study of this --SEA/αα carrier cohort indicated the high diversity of ζ-globin expression ranging from 0.00155 g/L to 1.48778 g/L. Significant positive correlation between ELISA and LC-MS/MS (R=0.400, p<0.001) was observed and it is more sensitive in distinguishing the samples with extreme expression of ζ-globin (R=0.650, p<0.001). CONCLUSION: Our study has reported reliable approaches for the quantification of ζ-globin and presented the expression patterns of ζ-globin among the --SEA/αα carrier population, which might lay a foundation on subsequent genotype-phenotype studies on mechanisms of delayed haemoglobin switch in α-thalassaemia.

Dexras1 Induces Dysdifferentiation of Oligodendrocytes and Myelin Injury by Inhibiting the cAMP-CREB Pathway after Subarachnoid Hemorrhage.

White matter damage (WMD), one of the research hotspots of subarachnoid hemorrhage (SAH), mainly manifests itself as myelin injury and oligodendrocyte differentiation disorder after SAH, although the specific mechanism remains unclear. Dexamethasone-induced Ras-related protein 1(Dexras1) has been reported to be involved in nervous system damage in autoimmune encephalitis and multiple sclerosis. However, whether Dexras1 participates in dysdifferentiation of oligodendrocytes and myelin injury after SAH has yet to be examined, which is the reason for creating the research content of this article. Here, intracerebroventricular lentiviral administration was used to modulate Dexras1 levels in order to determine its functional influence on neurological injury after SAH. Immunofluorescence, transmission electron microscopy, and Western blotting methods, were used to investigate the effects of Dexras1 on demyelination, glial cell activation, and differentiation of oligodendrocyte progenitor cells (OPCs) after SAH. Primary rat brain neurons were treated with oxyhemoglobin to verify the association between Dexras1 and cAMP-CREB. The results showed that Dexras1 levels were significantly increased upon in vivo SAH model, accompanied by OPC differentiation disturbances and myelin injury. Dexras1 overexpression significantly worsened OPC dysdifferentiation and myelin injury after SAH. In contrast, Dexras1 knockdown ameliorated myelin injury, OPC dysdifferentiation, and glial cell activation. Further research of the underlying mechanism discovered that the cAMP-CREB pathway was inhibited after Dexras1 overexpression in the in vitro model of SAH. This study is the first to confirm that Dexras1 induced oligodendrocyte dysdifferentiation and myelin injury after SAH by inhibiting the cAMP-CREB pathway. This present research may reveal novel therapeutic targets for the amelioration of brain injury and neurological dysfunction after SAH.

Clinical Predictive Models for Delayed Cerebral Infarction After Ruptured Intracranial Aneurysm Clipping for Patients: A Retrospective Study.

Objective: A nomogram was developed in this work to predict the probability of delayed cerebral infarction (DCI) after ruptured intracranial aneurysms (RIA) clipping. Methods: Clinical data of patients with intracranial aneurysm were obtained from the neurosurgery department of the First Affiliated Hospital of Chongqing Medical University from January 2016 to December 2020. A total of 419 patients receiving surgery of ruptured intracranial aneurysm clipping were included and a total of 37 patients with DCI were set as the observation group. The control group consisted of 382 patients without DCI. Risk factors of DCI were screened by univariate and multivariate logistic regression analysis and included in the nomogram. Results: Univariate analysis showed that female (P = 0.009), small aneurysm (P = 0.031), intraoperative aneurysm rupture (P = 0.007) and cerebral vasospasm (P < 0.001) were risk factors for postoperative DCI while smoking history (P = 0.044) were protective factors for postoperative DCI. Multivariate Logistic regression analysis showed that small aneurysm (P = 0.002, OR = 3.332, 95%-7.104), intraoperative aneurysm rupture (P = 0.004, OR = 0.122, 95%-CI, 0.029-0.504)and cerebral vasospasm (P < 0.001, OR = 0.153, 95%-CI, 0.070-0.333) were independent risk factors of postoperative DCI. The calibration curve of the probability of occurrence showed that the nomogram was in good correspondence with the observed results with a C-index of 0.766 (95% CI, 0.684-0.848). Meanwhile, the Decision curve analysis (DCA) showed that the established predictive model had a good clinical net benefit. Conclusion: The well-established nomogram is expected to be an effective tool to predict the occurrence of DCI after intracranial ruptured aneurysm and can be used to assist clinicians to develop more effective treatment strategies and improve the prognosis of patients.

Fluoride exposure induces lysosomal dysfunction unveiled by an integrated transcriptomic and metabolomic study in bone marrow mesenchymal stem cells.

Fluoride has received much attention for its predominant bone toxicity in the human body. However, the toxic mechanism of bone injury caused by fluoride exposure remains largely unclear. Bone marrow mesenchymal stem cells (BMSCs) are widely used as model cells for evaluating bone toxicity after environmental toxicant exposure. In this study, BMSCs were exposed to fluoride at 1, 2, and 4 mM for 24 h, and fluoride significantly inhibited cell viability at 2 and 4 mM. A multiomics analysis combining transcriptomics with metabolomics was employed to detect alterations in genes and metabolites in BMSCs treated with 2 mM fluoride. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of transcriptomics profiles identified "lysosomes" as the top enriched pathway, which was severely damaged by fluoride exposure. Lysosomal damage was indicated by decreases in the expression of lysosomal associated membrane protein 2 (LAMP 2) and cathepsin B (CTSB) as well as an increase in pH. Upregulation of the lysosome-related genes Atp6v0b and Gla was observed, which may be attributed to a compensatory lysosomal biogenesis transcriptional response. Interestingly, inhibition of glutathione metabolism was observed in fluoride-treated BMSCs at the metabolomic level. Moreover, an integrative analysis between altered genes, metabolites and lysosome signaling pathways was conducted. Palmitic acid, prostaglandin C2, and prostaglandin B2 metabolites were positively associated with Atp6v0b, a lysosome-related gene. Overall, our results provide novel insights into the mechanism responsible for fluoride-induced bone toxicity.

NUPR1 promotes the proliferation and metastasis of oral squamous cell carcinoma cells by activating TFE3-dependent autophagy.

Oral squamous cell carcinoma (OSCC) is the most common type of oral malignancy, and metastasis accounts for the poor prognosis of OSCC. Autophagy is considered to facilitate OSCC development by mitigating various cellular stresses; nevertheless, the mechanisms of autophagy in OSCC cell proliferation and metastasis remain unknown. In our study, high-sensitivity label-free quantitative proteomics analysis revealed nuclear protein 1 (NUPR1) as the most significantly upregulated protein in formalin-fixed paraffin-embedded tumour samples derived from OSCC patients with or without lymphatic metastasis. Moreover, NUPR1 is aberrantly expressed in the OSCC tissues and predicts low overall survival rates for OSCC patients. Notably, based on tandem mass tag-based quantitative proteomic analysis between stable NUPR1 knockdown OSCC cells and scrambled control OSCC cells, we confirmed that NUPR1 maintained autophagic flux and lysosomal functions by directly increasing transcription factor E3 (TFE3) activity, which promoted OSCC cell proliferation and metastasis in vitro and in vivo. Collectively, our data revealed that the NUPR1-TFE3 axis is a critical regulator of the autophagic machinery in OSCC progression, and this study may provide a potential therapeutic target for the treatment of OSCC.